Mammalian free glycan, glycocalyx and anti-glycan antibody in lupus

Bacteria and other microbes contain carbohydrates called glycans that allow the immune system to correctly identify them as enemies. All our own cells also carry glycans, which sometimes activate immune responses and may lead to chronic diseases such as lupus. We previously found that cells from patients with lupus show above-normal amounts of glycans. Moreover, blood from mice with lupus contains increased levels of the immune system proteins known as antibodies that target the glycans. Our new study will attempt to discover whether glycans from our cells and antibodies against them play a key role in lupus. We will determine the structure of glycans in the blood of patients with lupus and explain how they stimulate immune responses. To investigate potential new ways of diagnosing the disease, we will also determine which glycans make up the coating that is found on the surface of cells from patients with lupus and how are they different from healthy individuals. We also want to figure out which glycans the antibodies in patients’ blood target. Our studies may help researchers better understand glycans’ involvement in lupus and suggest potential new therapies for preventing these molecules from stimulating the immune system in the disease.

What this study means for people with lupus 

Our cells carry carbohydrates that usually enable the immune system to recognize the cells as harmless. Our study is testing whether immune cells in patients with lupus mistake the carbohydrates on our cells for those of harmful microbes and launch attacks. Our findings could identify better ways to diagnose lupus and suggest potential treatments that stop the immune system from targeting the carbohydrates.

Glycans from bacterial pathogens and fungi are well-known pattern-associated molecular patterns that are recognized by the host immunity. However, surprisingly little is known about whether mammalian self glycans also activate innate or adaptive immune responses in the settings of chronic diseases such as lupus. We recently showed that accumulation of immunogenic free glycans and anti-glycan antibodies leads to an autoimmune-prone state in mice. We also found that systemic lupus erythematosus (SLE) B cells contain significantly elevated levels of free glycans. Using a mammalian glycan microarray, we found that serums from common stains of spontaneous lupus mouse contain elevated levels of anti-glycan autoantibodies, similar to autoantibodies against protein antigens. This proposal will thus address a novel paradigm in which mammalian free glycans and anti-glycan antibodies are important targets in lupus. Our specific aims are: 1) Determine structure and bioactivity of free glycans in human SLE B cells. 2) Determine the glycocalyx of human SLE B cells using multi-color lectin FACS. 3) Examine free glycans and anti-glycan antibodies in human SLE serum. Several anti-glycan antibodies are being used as biomarkers for chronic immune disorders such as multiple sclerosis and Crohn’s disease. Monoclonal antibodies to glycans have also been developed to treat certain cancers. Studies proposed here will generate novel insights and therapeutic avenues that could be paradigm-shifting in how we view lupus diagnosis, stratification and therapy.